Heterocyclicalkyl esters of penicillin



number of carbon atoms United States Patent 2,694,062 HETEROCYCLICALKYL ESTERS OF PENICILLIN Erling Knud Frederiksen, Holte, and Erling Juhl Nielsen, Charlottenlund, Denmark, assignors to Lvens kemiske Fabrik ved A. Kongsted, Copenhagen, Denmark, a firm No Drawing. Application November 27, 1951, Serial No. 258,514

Claims priority, application Denmark July 7, 1949 11 Claims. (Cl. 260-2391) This invention relates to heterocyclicalkyl esters of penicillin and to the salts of such esters. The term heterocyclicalkyl is defined as an alkyl group substituted by a heterocyclic nitrogen-containing ring system joined to the alkyl group through nitrogen.

This application is a continuation-in-part of our copending applications Serial Nos. 168,384, filed June 15, 1950, and 246,148, filed September 11, 1951, both now abandoned, the latter application being a continuationin-part of the former. Serial No. 258,515 includes heterocyclic groups only when they are attached to quaternary nitrogen.

An object of this invention is to provide a series of novel penicillin compounds and acid addition salts of said compounds possessing beneficial physiological activity.

A further object of this invention is to provide a series of novel difiicultly soluble salts of heterocyclicalkyl esters of penicillin.

Another object of the invention is to provide a series of heterocyclicalkyl esters of penicillin in the use of which penicillin concentrates in various body tissues and fluids, for example lungs, brains and spinal fluid.

A still further object of this invention is to provide a series of compounds which have the property of maintaining useful blood levels and have depot eifect.

Another object of the invention is to provide for an injectable composition comprising the novel ester or salt in solution or suspension in a vegetable or animal oil, to which a small amount, say 1 to 3 per cent, of a salt, particularly a basic salt, of aluminium and a lipophilic acid, such as stearic acid, may be added.

Further objects of the invention will appear from the following, where a more detailed description of our invention is given together with results of clinical tests, and further the invention is illustrated by examples showing a convenient method of preparing said compounds, but we wish it to be understood that our invention is not to be considered limited thereby.

Some of the salts of the invention form crystals, while others form amorphous bodies, but in either case the salts have a full anti-bacterial efliect corresponding to that of the content of penicillin.

The compounds of the present invention are the aminoalcohol esters of penicillin having the structure Pen.COO.R.N.Y

in which Pen-COO is a penicillin with the hydrogen atom removed from the carboxyl group; R is an alkylene bridge having from 2 to 4 carbon atoms; N is the nitrogen atom of a 5- to 6-membered ring and Y is the remainder of a ring in which the other members of the ring in which the N occurs are selected from the group consisting of CR1R2-, =CR3, where R1, R2 and R3 are selected from the group consisting of hydrogen and alkyl groups containing 1 to 6 carbon atoms, N, NR4, O and S in a monocyclic radical, R4 being an alkyl group containing 1 to 6 carbon atoms, and in a. di-cyclic radical, the same and a pair of adjacent carbon atoms of a phenyl ring, and the acid addition salts of the said compounds innocuous to human beings.

The alkylene bridge (R) as stated contains from 2 to 4 carbon atoms, and the hydrogen atoms of the CH2 groups may be substituted by other alkyl groups containing from 1 to 6 carbon atoms, the total in the substituents not exceeding 6. Preferably the alkyl groups substituted in 2,694,062 Patented Nov. 9, 1954 the bridge will not contain more than two of such groups.

which may be attached to the same or diflerent carbon atoms.

Examples of the heterocyclic ring systems which may be present in the compounds of the invention are piperidine; alkyl substituted piperidine, where the total of carbon atoms in the substituents does not exceed 14, such as dimethyl piperidine, tetramethylpiperidine and hexylpiperidine or butylethylpiperidine; N-methyl and N-ethylpiperazine; pyrrolidine and substituted pyrrolidines where the total of carbon atoms in the substituents does not exceed 14; morpholine; imidazoline; thiazolidine; tetrahydroquinoline and -isoquinoline; isindoline; indoline; oxazolidine; of these the monocyclic ring systems are preferred. Advantageously the ring will be a piperidine ring, an alkyl substituted piperidine ring or pyrrolidine ring, where the substituents are methyl or ethyl and do not exceed 4, a morpholine ring or a N-methylor N-ethyl-piperazine ring.

While the preferred esters will be the esters of benzyl penicillin (penicillin G) and such esters will be more specifically referred to herein, the penicillin residue in the compound may, if desired, be that of any other penicillin, for example, penicillin O, K, F, dihydro-F and X as well as mixtures of various penicillins, for example a mixture obtained by submersed cultivation.

The following esters of benzyl penicillin are typical of the present invention: piperidinoethyl, pyrrolidinopropyl, morpholino-2,2-dimethylpropyl, 1-piperidino-2- hexylethyl, benzimidazolinobutyl, isindolinoethyl, indolinopropyl, oxazolidinoethyl, pyrrolidinoethyl, dimethylpiperidinoethyl, hexylpiperidinopropyl, l-piperidino-lmethylethyl, tetrahydroisoquinolinopropyl, tetrahydroquinolinobutyl, N-methylpiperazinoethyl, N-ethylpiperazino-Z-ethylbutyl, methylpiperidino-l-methyl-Z-ethylbutyl, N-methyl-imidazolinoethyl, N-ethyl-imidazolinopropyl, piperidino-l-methyl-propyl, piperidinopropyl, oxazolidino-4-ethyl-butyl, indolino-3-methyl-propyl, isindolino-2,2-diethylpropyl, benzimidazolino 3,3-dimethylbutyl, pyrrolidino-4-ethyl-butyl, tetrahydroquinolinoethyl, N-methyl-benzimidazolinopropy, N-ethyl-benzirnidazolinoethyl, isindolino-l-methyl-2-ethyl-ethyl, indolino-Z- ethyl-ethyl, 1-piperidino-2-methyl-ethyl.

The preferred esters of the new invention are benzylpenicillin piperidinoethyl ester, benzylpenicillin piperidinopropyl ester, methyl-substituted piperidinoethyl ester of benzylpenicillin, pyrrolidinoethyl ester of benzylpenicillin and pyrrolidinopropyl ester of benzylpenicillin.

The salts of the aminoalcohol esters of penicillin of the present invention are represented by the following formula:

where Pen, R, and Y are as defined in relation to the esters, and X is an acid residue innocuous to human beings.

By way of examples of acids, the following are mentioned, primary salts only being contemplated in the case of polybasic acids except for sulfuric acid, where only neutral salts are contemplated: hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, sulphuric, acetic, propionic, butyric, lauric, oleic, stearic, benzoic, naphtoic, o-aminobenzoic p-aminobenzoic, o-iodobenzoic, p-hydroxybenzoic, benzenesulphonic, toluenesulphonic, cinnamic, citric, fumaric, lactic, malic, maleic, mandelic, salicylic, p-aminosalicylic, acetylsalicylic, succinic and tartaric acids and penicillin. Of these salts the hydrochlorides, the hydrobromides, the hydroiodides and the citrates are preferred.

The compounds of the invention may be prepared by bridge contains two to four carbon atoms, where the.,carbon atom next to the oxygen has at least one unsubstituted hydrogen atom, the esters are prepared by reacting a penicillin salt and a halide of the trialgylamine (the heterocyclicalkyl halide) corresponding-to the ester desired, such halides being prepared, if desired, from the corresponding aminoalcohol by well-known procedures.

For example, a penicillin salt is suspended or dissolved in a suitable diluting agent in which the ester formed is soluble, such as one of the lower alcohols, for instance methanol, ethanol or isopropanol; a ketone such as acetone, methylethyl ketone, diisopropylketone and acetylacetone; hydrocarbons, such as benzene, toluene, xylene, and chlorinated hydrocarbons, such as chloroform and carbon tetrachloride; diethylacetamide or tetrahydrofuran and the like. The halide may then be added, preferably in excess, for example to per cent, after which the mixture is allowed to react under agitation by stirring or shaking, if desired. The temperature at which the reaction takes place may be varied as desired, so long as it is not sufficiently high to cause decomposition of the penicillin salt or the penicillin ester formed. Generally the reaction will be conducted between about room temperature, although it may be lower, and about 80 C. to 90 C. Preferably, the reaction is conducted under reflux at a temperature between about 40 C. and about 70 C. under which conditions good yields of the product Will generally be obtained in from /2 to 5 hours.

The reaction may be illustrated by the following reaction using sodium penicillin and piperidinoethyl chloride as typical.

The sodium chloride or other salt formed by the reaction is removed by filtration or other suitable means. When it is desired to isolate the ester, it may be obtained by evaporation of the solvent from the solution in which the ester is formed, or preferably it is obtained by treatment of a soluble salt of the ester, such as hydrochloride or citrate, with an alkaline material, such as caustic soda, followed by extraction with an organic solvent, in which the ester is soluble, and evaporating the solvent.

In preparing salts of the esters, the solution, in which the ester is formed, may be treated with an acid which forms a salt of the ester, preferably an alcoholic solution of hydrochloric, hydroiodic or citric acid. Preferably when a salt diflicultly soluble in water is to be formed, such as the hydrobromide or hydroiodide of piperidinoethylester of penicillin G, the hydroiodide of morpholinoethylester of penicillin G or the hydroiodide of l-morpholino-2.Z-dimethylpropylester of penicillin. G, it is produced by adding an aqueous solution of a water soluble salt of the acid to the solution of the soluble salt of the ester, which may previously have been diluted with water. The difficultly water soluble salt of the penicillin ester precipitates and is removed from the solution by filtering, decanting, centrifuging or the like.

In place of the sodium salt of penicillin given as an example in the above equation any soluble or insoluble penicillin salt may be employed, for example, the potassium, ammonium, calcium, barium, silver, procaine, triethylamine or N-ethyl-piperidine salt. Instead of employing the chloride of the tertiary amine, the other halides may be used, particularly the bromide.

The above method for producing the penicillin esters is not claimed herein, but is the subject matter of our co-pending application Serial No. 258,513, filed November 27, 1951.

In place of reacting the penicillin salt with the halide of the tertiary amine, the compounds of the present invention may be produced by reacting penicillin anhydride or a mixed anhydride of penicillin and acetic acid directly with the aminoalcohol corresponding to the ester desired. The mixed anhydride is prepared by reacting a penicillin salt in a suitable organic solvent with acetyl chloride at room temperature or slightly lower, for instance 5 C.l0 C. The mixed anhydride in the solution is then reacted with aminoalcohol at about the same temperature, the solution is evaporated to form a syrup, the residue is washed with petroleum ether, for

example, and then extracted with a solvent, such as ab solute ethanol. After removal of the chloride (formed by the cation of the penicillin salt and chlorine from the acetylchloride) by filtration or in other suitable manner, the solution is neutralized with alcoholic hydrogen chloride, if a hydrochloride of the ester is to be produced. The crystallisation may then be brought about by adding a suitable amount of ether. The method involving the use of penicillin anhydride is described in 1. AC. S. 70, pages 2964-2966 (1948). In either method, if the ester itself is desired, it may be obtained from the solution, in which it is formed, or from the salt, by the method described above in connection with the preparation of the compound using a halide of a trialkyl amine.

The capacity of the compounds of the invention to accumulate in the lung tissue is illustrated by the fol lowing biological test:

In a number of rats weighing 200 g. each, 25,000 units of penicillin were intramuscularl-y injected in the form of the compounds mentioned in the table given below. One hour after the injection the rats were killed and the concentration CB of penicillin in the blood (in units per cc.) and Co in the lung tissue (in units per g.) was determined.

TABLE Compounds (injected as the hydroiodide) 0 00 g:-

Benzylpenicillinester of l-piperidinoethanol- 2 17 83 4. 9 Benzylpenicillinester of 1-morpholiuo-2, 2-

dimethyl-propanol-(3) 1. 0 3. 6 3. 6 Benzylp enicillinester of l-piperidino-2-methylethyl 6. 2 26 4. 2 Allylmercaptornethylpen piperidincethanol-(2) 15 75 5. 0 Sodium salt of benzylpenicillin 30 11 0. 4

1 Ester of penicillin 0.

We have found that by suspending salts of our new amino esters of penicillin in a vegetable or animal oil in which is dissolved a quantity, for example 1 to 3 per cent, of a salt of aluminum and a lipophilic acid, particularly a basic salt, such as aluminium monostearate or aluminium distearate, we can obtain compositions having a more enduring protracted effect than that obtained 'by injection of said salts suspended in saline.

Instead of stearates other salts of fatty acids having 12 to 22 carbon atoms in the molecule may be used. Examples of a suitable vegetable oil are peanut oil, cottonseed oil, sesame oil and olive oil.

Furthermore, we have found that the esters themselves are soluble in certain liquids, particularly animal and vegetable oils and liquids of similar character, such as the ethyl ester of oleic acid and di-ethyl succinate. Such solutions, either pure or as part of a composition of matter, are often particularly valuable as injectable therapeutic compositions.

The invention is further illustrated by the following examples.

Exaniple 1 BENZYL PENICILLIN PIPERIDINOETHYL ESTER- HYDROBROMIDE 7.4 grams of the potassium salt of benzylpenicillin are suspended in 40 ccs. of acetone and 3 grams of piperidinoethyl chloride are added. The mixture is refluxed for 3 hours and, after cooling, the potassium chloride is removed, .the filtrate is evaporated in vacuum till it becomes a syrup, and this is dissolved in 20 ccs. of ethanol. Alcoholic hydrogen chloride solution is added until .a sample diluted with water shows pH:4.5 to 5. On addition of ether, benzylpenicillin-piperidino-ethyl ester hydrochloride is precipitated in an amorphous state. After removal of the ether, the hydrochloride is dissolved in 20 ccs. of water, and a solution of 4.8 grams of potassium bromide in 15 cos. of water is added. On standing at 0 C. for 12 hours, benzyl penicillin-piperidinoethyl ester-hydrobromide crystallizes. The yield is 6 grams, corresponding to 57 per cent. The melting point is 135.5 to l36.5 C.

all

ing for 12 hours at Example 2 ALLYLMERCAPTOMETHYLPENICILLIN-PIPERIDINO- ETHYL ESTER-CITRATE tion, and a solution of 4.2 grams of the monoahydrate of citric acid in 20 ccs. of acetone is added. After stand- C. the crystalline penicillin O- piperidinoethyl ester-citrate is removed by filtration. Yield: 8.9 grams or 70 per cent of the theoretical. Melting point: 104 to 105 C.

Example 3 BENZYLPENICILLIN MORPHOLINOETHYL ESTER- HYDROCHLORIDE 7.1 grams of the sodium salt of benzylpenicillin are suspended in 40 ccs. of acetone and 3 grams of morpholinoethyl chloride are added. The mixture is refluxed for 12 hours. After cooling, sodium chloride is removed by filtration. The filtrate is evaporated in vacuum until the volume is 25 ccs., and 100 ccs. of ether are added. The precipitate, which is formed, is removed by filtration, and the filtrate is evaporated in vacuum to a syrup which is dissolved in 25 ccs. of anhydrous ethanol. Hydrogen chloride in alcoholic solution is added until the pH of a sample diluted with water is about 4 to 5. After addition of 50 ccs. of ether, the mixture is left standing for 12 hours at 0 C. Benzylpenicillin-morpholinoethyl ester hydrochloride crystallizes and is removed by filtration. Yield: 5.2 grams (54 per cent). Melting point: 137 to 138 C.

Example 4 BENZYLPENICILLIN-l- 2-HEXYLPIPERIDINO -ETHYL- (2) ESTER-HYDROCHLORIDE 20 grams of the sodium salt of penicillin G are suspended in 300 ccs. of anhydrous acetone and 16.6 grams of 1-(2-hexylpiperidino)-2-chlorethyl are added. The mixture is stirred for several days at room temperature or refluxed until the required interaction has been efiected, the precipitation of the sodium chloride being an indication of the interaction. After removal of the sodium chloride by filtration, the filtrate is evaporated in vacuum at low temperature (less than 30 C.) until it becomes a syrup. The syrup is dissolved in ether and the solution is filtered. Dry hydrogen chloride is added to the ether solution and the resulting hydrochloride product, which precipitates, is isolated by filtration or removal of the mother liquor by decantation. The reaction product is benzylpenicillin-1-(2'-hexylpiperidino)- ethyl-(2) ester-hydrochloride.

Example 5 BENZYLPENICILLIN-1- (2'-HEXYLPIPERIDINO -ETHYL- (2) ESTER-HYDROIODIDE allowed to stand until the hydroiodide salt precipitates.

The product is then collected and dried.

Example 6 BENZYLPENICILLIN-l- (2',6-DIMETHYLPIPERIDINO ETHYL- (2) ESTER-HYDRO CHLORIDE This compound was prepared using a procedure identical with that'of Example 4 above, with the exception that 12.8 grams of l (,8 chlorethyl) 2,6-dimethyl-pi- .peridine was reacted with the sodium salt of penicillin G.

The corresponding hydroiodide may be formed from the hydrochloride product by following the procedure of Example 5.

Example 7 BENZYLPENICILLIN-1-(2,2 ',4',6-TETRAMETHYLPIPER- IDIN O -ETHYL- (2 ESTER-HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, with the exception that 14.9 grams of I-(B-chlorethyl)-2,2,4,6-tetramethylpiperidine was reacted with the sodium salt of penicillin The corresponding hydroiodide may be prepared from the hydrochloride product by following the procedure of Example 5.

' Example 8 BENZYLPENICILLIN 1 -(1,2,3',4-TETRAHYDROISO- QUINOLINE)I-ETHYL-(2) ESTER-HYDROCHLORIDE v This compound was prepared using a procedure identical with that of Example 4 above, with the exception that 14 grams of Z-(B-chlorethyl)-l,2,3,4-tetrahydroisoquinoline was reacted with the sodium salt of penicillin G. The corresponding hydroiodide may be prepared from the hydrochloride product by following the procedure of Example 5.

Example 9 BENZYLPENICILLIN-PYRROLIDINOETHYL E STER- HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, with the exception that 9.6 grams of ,B-chlorethyl pyrrolidine was reacted with the sodium salt of penicillin G. The corresponding hydroiodide may be prepared from the hydrochloride product by following the procedure of Example 5.

Example 10 BEN ZYLPENICILLIN -N-METHYLIHIDAZOLINEETH YL ESTERJSIYDROCHLORIDE' Example 11 BEN ZYLPENICILLIN -1-PIPERIDIN O-2-METHYLETHYL ESTER-HYDRO CHLORIDE 7.4 grams of the potassium sadt of benzylpenicillin are suspended in 40 ccs. of acetone, and 3.2' grams of lpiperidino-Z-methylethyl chloride are added. The mixture is refluxed for 3 hours. After cooling, potassium chloride is removed by filtration, and the filtrate is evaporated in vacuum to dryness. The residue is dissolved in 50 ccs. of ethanol, and alcoholic solution of hydrogen chloride is added until the pH of a sample diluted with water is about 5. On addition of 200 ccs. of ether the amorphous benzylpeni'cillin-l-piperidino 2 methylethyl ester-hydrochloride is precipitated. Yield: 6.7 grams (68 per cent).

Example 12 BEN ZYLPENICILLIN -1-PIPERIDIN OP'ROPYL- (3 ESTER-HYDROCHLORIDE BENZYLPENICILLIN-l-PIPERIDINO-4-METHYL-BUTYL- (4) ESTER-HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, withthe exception that an equimolar quantity of a-chloramyl-piperidine was reacted with the sodium salt of penicillin G. The corresponding hydroiodide may be prepared from the hydrloclgloride product by following the procedure of Examp e Example 14 BENZYLPENICILLIN-l-MORPHOLINO-2,Z-DIMETHYL PROPYL- 3) ESTE-R-HYDROIODIDE A mixture of 21.36 grams of the sodium salt of benzylpenicillin and 12.13 grams of 1-morpholino-2,2-dimethylpropyl chloride in ccs. of acetone is refluxed for 12 hours. Sodium chloride is removed by filtration, and the filtrate is evaporated in vacuum. To the residue, 200 ccs. of ether. are added, and the impurities not soluble rated in vacuum, and the residue is dissolved in 60 cos.

of anhydrous ethanol. Hydrogen chloride in alcoholic solution is added until pH of a sample diluted with water is about 5. To the solution, 100 cos. of water are added and then 48 cos. of per cent potassium iodide solution. After standing for 12 hours at 0 C., the crystalline benzylpenicillin l-morpholino-2,2-dimethylpropl-(3) este -hydroiodide precipitates and is washed with methanol and ether. Yield: 9.7 grams (26.5 per cent). Melting point: 168 to 169 C.

Example 15 BENZYLPENICILLIN-L (1,2',3,4-TETRAHYDROQUIN- OL1NE)-ETHYL-(2) ESTER-HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, with the exception that an equimolar quantity of l-(fi-chjlorethyh- 1,2,3,4-tetrahydroquinoline was reacted with the sodium salt of penicillin G. The corresponding hydroiodide may be prepared from the hydrochloride product by following the procedure of Example 5.

Example 16 BENZYLPENICILLIN-1-PIPERIDINOHEPTYL- (3) ESTE-R HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, with the exception that an equimolar quantity of l-(3-chlorheptyl)- piperidine was reacted with the sodium salt ot penicillin G. The corresponding hydroiodide may be prepared from a hydrochloride product by following the procedure of Example 5.

Example 17 BENZYLPENICILLINl-HEXYL 2-PIPERIDINOETHYL- 1) ESTER-HYDROCHLORIDE BENZYLPENICILLIN-l- (N '-ETHYLBENZIMIDAZOLINO) ETHYL- (2) ESTER-HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, with the exception that an equimolar quantity of l-(B-chlorethyD-S- ethylbenzimidazoline was reacted with the sodium salt of penicillin G. The corresponding hydroiodide may be prepared from the hydrochloride product by following the procedure of Example 5.

Example 19 BENZYLPENICILLIN-l-ISINDOLINOETHYL (2) ESTER- HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, with the exception that an equimolar quantity of Z-(fi-chlorethybisindoline was reacted with the sodium salt of penicillin G. The corresponding hydroiodide may be prepared from the hydrochloride product by following the procedure of Example 5.

Example 20 BENZYLPENICILLIN-l-INDOLINOETHYL- (2) ESTER- HYDROCHLORIDE Example 5.

Example 21 BEN ZYLPENICILLIN-1-OXAZOLIDINOETHYL- (2) ESTER- HYDROCHLORIDE This compound was prepared using a procedure identical with that of Example 4 above, with the exception that an equimolar quantity of 3-(p-chlorethy1)- in ether are removed by filtration. The filtrate is evapo- 8 oxazolidine was reacted with the sodium salt of penicillin G. The corresponding hydroiodide may be prepared from the hydrochloride product by following the procedure of Example 5.

Example 22 BENZYLPENICILLINl-PIPERIDINOETHYL- (2) ESTER- BEN ZOATE The hydrochloride product of Example 1 is dissolved in water and one equivalent of sodium hydroxide solution is added. The benzylpenicillin-piperidinoethyl ester is isolated by extraction with ether. The resulting solution is dried over sodium sulfate, after which the solvent removed by distillation in vacuo. The thus obtained free penicillin ester is dissolved in ethanol and to this solution is added one equivalent of benzoic acid. The solvent is removed in vacuo and the resulting product is crystallized from ether or may be used as such. The product is benzylpenicillin-piperidinoethyl ester-benzoate.

Example 23 BENZYLPENICILLIN-PIPERIDINOETHYL ESTER- SUCCINA'IE This compound may be prepared by isolating the free penicillin ester as in Example 22, and forming the salt as described in Example 22, with the exception that two equivalents of succinic acid is used instead of benzoic acid, to form the desired salt.

Example 24 BENZYLPENICILLIN-PIPERIDINOETHYL ESTER- PHOSPHATE This compound may be prepared by isolating the free penicillin ester as in Example 22, and forming the salt as described in Example 22, with the exception that three equivalents of phosphoric acid is used instead of benzoic acid, to form the desired salt.

Example 25 BENZYLPENICILLIN-PIPERIDINOETHYL ESTER- SULFATE This compound may be prepared by isolating the free penicillin ester as in Example 22, and forming the salt as described in Example 22, with the exception that one equivalent of sulfuric acid is used instead of benzoic acid, to form the desired salt.

Example 26 O-PENICILLIN-PIPERIDINOETHYL ESTER-HYDRO- CHLORIDE This compound may be prepared using the procedure of Example 1, except that an equimolar quantity of the sodium salt of penicillin O is suspended in 300 cc. of anhydrous acetone and reacted with 10.6 grams of N- B-chlorethyl) -piperidine.

Example 27 K-PENICILLIN-PIPERIDINOETHYL E STER-HYDRO- CHLORIDE This compound may be prepared using the procedure of Example 1, except that an equimolar quantity of the sodium salt of penicillin K is suspended in 300 cc. of anhydrous acetone and reacted with 10.6 grams of N- (fi-chlo rethyl) -pip eridine.

Example 28 OIL SUSPENSION OF BENZYLPENICILLIN-PIPERIDINO- ETHYL ESTER-HYDROIODIDE To one liter of peanut oil is added 20 grams of aluminium mono-stearate and the mixture is heated slowly with stirring until a clear solution is obtained. The heating is continued until the solution has reached a temperature of C. and it is kept at this temperature for one-half to one hour and it is then cooled to 25 C. To the cooled solution is added 390 grams of benzylpenicillin-piperidinoethyl ester hydroiodide having a article size of 2 to 5p. The resulting solution may be used directly for intramuscular injection.

We claim:

1. As new products, the hydriodides of amino esters of penicillin represented by the formula:

Pen COO.R.N.Y, HI

where Pen COO represents penicillin with the hydrogen atom removed from the carboxyl group; where R repre sents alkylene containing 2 to 4 carbon atoms in a straight chain, the total number of carbon atoms in R not exceeding 10; and where NY is a radical selected from the group consisting of N-alkyl piperazino in which the alkyl groups contain from 1 to 2 carbon atoms, and piperidino, morpholino, and pyrrolidino radicals, and the three last named radicals substituted with an alkyl group containing 1 to 2 carbon atoms.

2. As new products, the hydriodides of amino esters of penicillin represented by the formula:

CHz-CHZ Pen COO.R.N CH2, HI

OH2 CH2 CHPCH? NR HI CH2-C 2 where Pen COO represents penicillin with the hydrogen removed from the carboxyl group; and where R represents alkylene containing 2 to 4 carbon atoms in a straight chain, the total number of carbon atoms in R not exceeding and R5 is an alkyl group of from 1 to 2 carbon atoms.

Pen 0 O 0.R.N

5. The compounds of claim 4, wherein Pen CO0 is the acyloxy residue of benzylpenicillin.

As new products, the hydriodides of amino esters of penicillin represented by the formula:

CHr-CHz Pen COO.R.N HI

CH2CH2 ethanol.

9. The hydroiodide of the penicillin-1-morpholino-2,2- dimethylpropyl- 3 esters.

10. The hydroiodide of the penicillin-l-N-methylpiperazinoethyl-(2) esters.

11. The hydroiodide of the penicillin-l-N-ethylpiperidinoethyl-(2) esters.

Kirchner et al.: J. Org. Chem, vol. 14, May 1949, pp. 390-2. 

1. AS NEW PRODUCTS, THE HYDROIODIDES OF AMINO ESTERS OF PENCILLIN REPRESENTED BY THE FORMULA: 